1. Field of the Invention
The present invention is related to rodenticidal compositions containing 2-chloro-1,4-naphthoquinone and closely related derivatives thereof. The invention is also related to methods of killing rodents using the compounds disclosed herein.
2. Description of the Prior Art
The control of rodent populations is a problem in many areas of the world. In addition to their attacks on man's food, rodents also harbor vectors of many diseases of man and domesticated animals. Rodent-derived diseases include Bubonic plague, Weils disease, endemic typhus, scrub typhus, Rocky Mountain spotted fever, and various salmonella-derived diseases which are contracted by handling objects contaminated by rodent urine or feces.
A number of chronic poisons had been developed for killing rodent pests. Chronic poisons are those which generally require several feedings to produce a lethal effect. One type of chronic poison is the group having anticoagulant activity. There are a wide range of chronic anticoagulant rodenticides, and these each share a common mode of action involving antagonism of Vitamin K action.
Vitamin K.sub.1 is an important blood coagulation co-factor. Vitamin K.sub.1 is essential for coagulation because of its role in the synthesis of four clotting proteins, all of which are capable of binding calcium and are essential for the cascade mechanism leading to the formation of thrombin and thus, blood coagulation. Anticoagulants interfere with the metabolism of Vitamin K.sub.1, resulting in decreased Vitamin K-dependent carboxylation of the clotting factors. Without vitamin K.sub.1 to act as a co-factor, thrombin formation is inhibited, the blood loses its ability to coagulate, and death can result from spontaneous hemorrhaging.
A number of compounds which are structurally related to vitamin K can function as anti-coagulants, among which those with coumarin ring systems are notable. Two anticoagulants of note are dicumarol (a clinically effective anticoagulant) and warfarin (used both clinically and as a rodenticide).
The use of the natural anticoagulant dicoumarol as a rodenticide was first described in 1948 by O'Connors (Research 1, 334 (1948)). Other 4-hydroxy-coumarins have been described, some of which are more effective than warfarin itself. See Kirk Othmer's Encyclopedia of Chemical Technology, Vol. 18, 302-320, 1981, which is hereby incorporated by reference.
Another type of anticoagulant rodenticide is based on indanedione. Some of these compounds are as effective as warfarin or the other 4-hydroxy-coumarins although few, if any, of these compounds are used commercially.
Lowenthal, in a series of reports, has shown that a competitive vitamin K antagonist which is neither a hydroxy coumarin or an indanedione is also an active anticoagulant. (See J. Pharmacol. Exp. Ther. 157 (3), 672-80, 1967; Experientia 16, 428-9, 1960; and Canadian Journal Chemistry, 48, 3957-58, 1970.) The compounds studied in these references are vitamin K.sub.1 analogues, primarily 2-chloro-3-phytyl-1,4-naphthoquinone. In this analogue, a chlorine atom is substituted for the methyl group of Vitamin K.sub.1. Lowenthal's work was continued by Suttie and co-workers and reported in Science, 180, 741-43, 1973 and patented by Suttie in U.S. Pat. No. 4,021,568. Suttie disclosed a rodenticide based on the chloro analogue of vitamin K.sub.1 and showed that it was effective against strains of wild rats that were resistant to the anticoagulant action of coumarins and derivatives of indanedione. Suttie further showed that the compound could be used either alone or in combination with warfarin. However, this compound proved to be difficult to synthesize and chemically unstable. Accordingly, although it exhibits a relatively high degree of toxicity to warfarin-resistant rats, it has not found overwhelming usage because of these drawbacks. None of the compounds disclosed herein contain the phytyl side-chain of the compounds investigated by Lowenthal and Suttie.
2-chloro-1,4-naphthoquinone, one of the compounds of the present invention, is a known compound, although not for the purpose of a rodenticide. For example, Perumal showed a relatively simple synthesis of this compound in Tetrahedron Letters 33, 3099-3100, 1978. However, absolutely no utility was disclosed for the compound in this reference.
Guerillot-Vinet presented a study of the activity of anti-Vitamin K agents against bacteria. In passing, the reference indicates that 2-chloro-1,4-naphthoquinone has hemorrhagic activity. However, no further information on this compound is given in this reference, and it is unclear from the reference whether this compound would be suitable as a rodenticide.
There are several factors to be considered in deciding whether a particular compound which exhibits hemorrhagic activity can be used as a rodenticide. For example, such factors as stability of the compound in a food or bait environment, ease of synthesizing the compound, activity in vivo of the compound, the attractiveness of the compound to the animal to be poisoned, and the degree of selective toxicity of the compound for the rodent compared with both man and non-rodent wildlife animals. Guerillot-Vinet says nothing about the ability of this compound to be used as a rodenticide, and based on this reference, it is not predictable whether the compound could be so used. The present inventors quite surprisingly discovered that 2-chloro-1,4-naphthoquinone (and closely related derivatives) may be used in vivo as rodenticides and that both in vitro and in vivo activities of this compound are distinctly superior to warfarin and the chloro-K.sub.1 compound disclosed by Lowenthal and Suttie.
Using an in vitro rat hepatic vitamin K-dependent carboxylation system (described herein in the experimental examples), 2-chloro-1,4-naphthoquinone was found to be 45 times more potent than warfarin. An in vivo test of toxicity of 2-chloro-1,4-naphthoquinone in the rat, conducted by administering a single intravenous bolus dose showed that the acute lethal intravenous dose of this compound lies between 1 ng/kg and 1000 ng/kg. Thus, this compound is approximately 2.times.10.sup.5 to 2.times.10.sup.8 times more potent than intravenously administered warfarin, assuming an LD.sub.50 for warfarin of 0.2 mg/kg (the LD.sub.50 for warfarin may actually be as high as 10-50 mg/kg in rats, indicating an even larger difference in potency).
In view of the fact that new and more effective agents for the control of rodents are a constant necessity, due primarily to the fact that many strains of rodents have become resistant to known rodenticides, a need continues to exist for such agents. It was in this context that the present invention was achieved.